chr3-161503472-A-G

Position:

• chr3-161503472-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080440.1(OTOL1):​c.964A>G​(p.Thr322Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: OTOL1 NM_001080440.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0630

Genes affected

OTOL1 (HGNC:34071): (otolin 1) This gene encodes a secreted glycoprotein with a C-terminal complement Cq1-like globular domain that belongs to the C1q/tumor necrosis factor-related protein (CTRP) family. The encoded protein is expressed in the inner ear and forms a multimeric complex called the otoconia, together with cerebellin-1 and otoconin-90, as part of the otoconial membrane. It contains extensive posttranslational modifications including hydroxylated prolines and glycosylated lysines. Naturally occurring mutations in this gene are associated with abnormal otoconia formation and balance deficits resulting from vestibular dysfunction. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14481667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOL1	NM_001080440.1	c.964A>G	p.Thr322Ala	missense_variant	4/4	ENST00000327928.4	NP_001073909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOL1	ENST00000327928.4	c.964A>G	p.Thr322Ala	missense_variant	4/4	2	NM_001080440.1	ENSP00000330808.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.964A>G (p.T322A) alteration is located in exon 4 (coding exon 4) of the OTOL1 gene. This alteration results from a A to G substitution at nucleotide position 964, causing the threonine (T) at amino acid position 322 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.73
DANN	Benign	0.20
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.035	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.20
Sift	Benign	0.47	T
Sift4G	Benign	0.67	T
Polyphen		0.79	P
Vest4		0.085
MutPred		0.19		Loss of phosphorylation at T322 (P = 0.0026);
MVP		0.15
MPC		0.047
ClinPred		0.15	T
GERP RS		-2.8
Varity_R		0.028
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-161221260;